Genetic susceptibility of urolithiasis: comprehensive results from genome-wide analysis.

BACKGROUND: The pathogenesis of urolithiasis is multi-factorial and genetic factors have been shown to play a significant role in the development of urolithiasis. We tried to apply genome-wide Mendelian randomization (MR) analysis and figure out reliable gene susceptibility of urolithiasis from the largest samples to date in two independent genome-wide association studies (GWAS) database of European ancestry. METHODS: We extracted summary statistics of expression quantitative trait locus (eQTL) from eQTLGen consortium. Urolithiasis phenotype information was obtained from both FinnGen Biobank and UK Biobank. Multiple two-sample MR analysis with a Bonferroni-corrected P threshold (P < 2.5e-06) was conducted. The primary endpoint was the causal effect calculated by random-effect inverse variance weighted (IVW) method. Sensitivity analysis, volcano plots, scatter plots, and regional plots were also performed and visualized. RESULTS: After multiple MR tests between 19942 eQTLs and urolithiasis phenotype from both cohorts, 30 common eQTLs with consistent effect size direction were found to be causally associated with urolithiasis risk. Finally only one gene (LMAN2) was simultaneously identified among all top significant eQTLs from both FinnGen Biobank (beta = 0.6758, se = 0.0327, P = 6.775e-95) and UK Biobank (beta = 0.0044, se = 0.0009, P = 2.417e-06). We also found that LMAN2 was with the largest beta effect size on urolithiasis phenotype from the two cohorts. CONCLUSION: We for the first time implemented genome-wide MR analysis to investigate the genetic susceptibility of urolithiasis in general population of European ancestry. Our results provided novel insights into common genetic variants of urinary stone disease, which was of great help to subsequent researches.

Immunoglobulin heavy constant gamma 1 silencing decreases tonicity-responsive enhancer-binding protein expression to alleviate diabetic nephropathy.

AIMS/INTRODUCTION: The molecular mechanisms of diabetic nephropathy (DN) are poorly identified. However, the advantage of an increasing amount on microarray data of diabetic nephropathy intrigued us to explore the mechanisms based on bioinformatics prediction for diabetic nephropathy. MATERIALS AND METHODS: Bioinformatics analysis was conducted to screen the hub genes associated with diabetic nephropathy. The average human renal tubular epithelial cells were exposed to high glucose (HG) to generate an in vitro cell model. In addition, a mouse model of diabetic nephropathy was established using a high-fat diet and streptozotocin injection. Finally, the shRNA targeting immunoglobulin heavy constant gamma 1 (IGHG1) was introduced in vitro and in vivo to illustrate its effect on downstream factors and on the development diabetic nephropathy. RESULTS: Bioinformatics analysis revealed that IGHG1, TRIM11 (tripartite motif protein 11), and TonEBP are highly expressed in diabetic nephropathy. In vitro cell experiments demonstrated that IGHG1 positively regulates the expression of TRIM11 and TonEBP (tonicity-responsive enhancer binding protein) in HK2 cells treated with high glucose. Furthermore, TRIM11 upregulates the expression of TonEBP through activation of the MEK/ERK (mitogen-activated protein kinase/extracellular signal-regulated kinase) signaling pathway in HK2 cells treated with high glucose. In vivo, animal experiments further confirmed that silencing IGHG1 could prevent the occurrence and development of diabetic nephropathy. CONCLUSION: The silencing of IGHG1 alleviated diabetic nephropathy by inhibiting the TRIM11/MEK/ERK axis and by downregulating TonEBP.

LI-RADS LR-5 on contrast-enhanced ultrasonography has satisfactory diagnostic specificity for hepatocellular carcinoma: a systematic review and meta-analysis.

Background: The Liver Imaging Reporting and Data System (LI-RADS) for contrast-enhanced ultrasonography (CEUS) was invented to define suspected liver nodules based on their imaging characteristics. Among the categories of nodules of LI-RADS for CEUS, LR-5 is generally considered to be definitely malignant; however, the exact diagnostic performance of this liver nodule category has varied between different studies. Therefore, we performed this systematic review and meta-analysis to calculate the pooled diagnostic sensitivity, specificity based on important data extracted from some influential clinical studies. Methods: A preliminary search of national and international databases, including PubMed/Ovid Medline, Embase, Cochrane Library, Web of Science, and Wan Fang Data, for relevant studies on CEUS LI-RADS LR-5 published between January 2017 and June 2021 was conducted. A literature screening and selection process was undertaken to evaluate the relevance of the articles, and studies deemed eligible for inclusion in the review were subsequently identified. The updated Quality Assessment of Diagnostic Accuracy Studies (QUADAS-2) tool was applied as the main method to assess the risk of bias and applicability of the studies. A meta-analysis of the diagnostic sensitivity and specificity of CEUS LI-RADS LR-5 was performed using the free software, Meta-DiSc 1.4 (Ramóny Cajal Hospital, Madrid, Spain). The area under curve (AUC) was calculated to help determine the diagnostic efficiency. A meta-regression analysis was also performed to identify factors that could have contributed to heterogeneity between the studies. Results: Twelve studies with 20 observations focused on investigating the relative diagnostic performance of the CEUS LI-RADS LR-5 category for hepatocellular carcinoma (HCC) detection were finally recruited into the systematic review and meta-analysis. The pooled diagnostic sensitivity was 0.71 [95% confidence interval (CI): 0.69-0.72], with heterogeneity (I2) of 88.4%, and the pooled specificity was 0.93 (95% CI: 0.92-0.95), with an I2 of 71.2%. Study heterogeneity was observed and statistically correlated with the number of centers and the reference standard. Conclusions: The CEUS LI-RADS LR-5 category has satisfactory diagnostic efficacy for HCC, as evidenced by an acceptable diagnostic sensitivity of 0.71 and a good diagnostic specificity of 0.93.

Protein kinase C beta relieves autism-like behavior in EN2 knockout mice via upregulation of the FTO/PGC-1α/UCP1 axis.

Increasing evidence suggests that disruption of neuron activity contributes to the autistic phenotype. Thus, we aimed in this study to explore the role of protein kinase C beta (PKCß) in the regulation of neuron activity in an autism model. The expression of PKCß in the microarray data of autism animal models was obtained from the Gene Expression Omnibus database. Then, mice with autism-like behavior were prepared in EN2 knockout (-/- ) mice. The interaction between PKCß on fat mass and obesity-associated protein (FTO) as well as between PGC-1α and uncoupling protein 1 (UCP1) were characterized. The effect of FTO on the N6 -methyladenosine (m6A) modification level of proliferator-activated receptor gamma coactivator 1-alpha (PGC-1α) was assayed. Following transfection of overexpressed PKCß and/or silenced UCP1, effects of PKCß and UCP1 in autism-like behaviors in EN2-/- mice were analyzed. Results showed that PKCß was downregulated in EN2-/- mouse brain tissues or neurons. PKCß promoted the expression and stability of FTO, which downregulated the m6A modification level of PGC-1α to promote its expression. Moreover, PGC-1α positively targeted the expression of UCP1. PKCß knockdown enhanced sociability and spatial exploration ability, and reduced neuron apoptosis in EN2-/- mouse models of autism, which was reversed by UCP1 overexpression. Collectively, PKCß overexpression leads to activation of the FTO/m6A/PGC-1α/UCP1 axis, thus inhibiting neuron apoptosis and providing neuroprotection in mice with autism-like behavior.

Are adrenergic α1- antagonists beneficial for the access of retrograde ureteral access sheath or semi-rigid ureteroscope access? A systematic review and meta-analysis.

Introduction: To evaluate the clinical benefit of preoperative adrenergic α1-antagonist therapy in the management of upper urinary calculi. Materials and methods: Publications were searched for The Cochrane Central Register of Controlled Trials, EMBASE, and MEDLINE until 1 March 2022 that related to the adrenergic α1- antagonist intake as adjunctive therapy before retrograde surgery. Dichotomous data were reported with risk ratios (RR) with 95% confidence intervals (CIs) and the continuous data were reported with mean difference (MD) with 95% CIs. Results: There were nine studies with 867 patients included in this meta-analysis. Preoperative adrenergic α1- antagonists could significantly elevate the compared with the placebo. Higher successful access rate to the stone was found in patients who received preoperative adrenergic α1- antagonists than those who received the placebo (RR 1.24; 95% CI 1.17-1.33). Besides, the application of preoperative adrenergic α1- antagonists can also elevate 4th-week stone-free rate (RR 1.20; 95% CI 1.12-1.28), decrease postoperative analgesia (RR 0.30;95% CI 0.20-0.46) and result in a lower risk of overall complications (RR 0.38; 95% CI 0.24-0.61). Conclusion: Preoperative adjunctive adrenergic α1- antagonist therapy is effective and safe in the management of retrograde surgery with a higher successful access rate and lower risk of severe complications.

Suppressive role of E3 ubiquitin ligase FBW7 in type I diabetes in non-obese diabetic mice through mediation of ubiquitination of EZH2.

The current study tried to uncover the molecular mechanism of E3 ubiquitin ligase F-box and WD repeat domain-containing 7 (FBW7) in a heritable autoimmune disease, type I diabetes (T1D). After streptozotocin-induced T1D model establishment in non-obese diabetic (NOD) mouse, the protein expression of FBW7, enhancer of zeste homolog 2 (EZH2), and Zinc finger and BTB domain containing 16 (ZBTB16) was quantified. Next, splenocytes and pancreatic beta cells were isolated to measure the production of pro-inflammatory cytokines in splenocytes, as well as islet beta-cell apoptosis. Additionally, the stability of EZH2 induced by FBW7 was analyzed by cycloheximide chase assay. The binding affinity of FBW7 and EZH2 and the consequence of ubiquitination were monitored by co-immunoprecipitation assay. Last, a chromatin immunoprecipitation assay was employed to analyze the accumulation of EZH2 and H3K27me3 at the ZBTB16 promoter region. Our study demonstrated downregulated FBW7 and ZBTB16 and upregulated EZH2 in diabetic NOD mice. Overexpression of FBW7 in the NOD mice inhibited pro-inflammatory cytokine release in the splenocytes and the apoptosis of islets beta cells. FBW7 destabilized EZH2 and accelerated ubiquitin-dependent degradation. EZH2 and H3K27me3 downregulated the ZBTB16 expression by accumulating in the ZBTB16 promoter and methylation. FBW7 upregulates the expression of ZBTB16 by targeting histone methyltransferase EZH2 thus reducing the occurrence of T1D.

Corrigendum: Histone Deacetylase 3 Aggravates Type 1 Diabetes Mellitus by Inhibiting Lymphocyte Apoptosis Through the microRNA-296-5p/Bcl-xl Axis.

[This corrects the article DOI: 10.3389/fgene.2020.536854.].

miR-485 inhibits histone deacetylase HDAC5, HIF1α and PFKFB3 expression to alleviate epilepsy in cellular and rodent models.

We investigated the role of microRNA (miR)-485 and its downstream signaling molecules on mediating epilepsy in cellular and rat models. We established a cellular epilepsy model by exposing hippocampal neurons to magnesium and a rat model by treating ICR mice with lithium chloride (127 mg/kg) and pilocarpine (30 mg/kg). We confirmed that miR-485 could bind and inhibit histone deacetylase 5 (HDAC5) and then measured expression of miR-485 and in mice and cells. Cells were transfected with overexpression or knockdown of miR-485, HDAC5, hypoxia-inducible factor-1alpha (HIF1α), or 6-phosphofructo-2-kinase/fructose-2,6-biphosphatase 3 enzyme (PFKFB3) to verify their roles in apoptosis, oxidative stress, and inflammation in epileptic hippocampal neurons. Binding relationship between miR-485, HDAC5, HIF1α, and PFKFB3 was verified. Oxidative stress and inflammation marker levels in epilepsy model mice were assessed. miR-485 was downregulated and HDAC5 was upregulated in cell and animal model of epilepsy. Seizure, neuronal apoptosis, oxidative stress (increased SOD and GSH-Px expression and decreased MDA and 8-OHdG expression) and inflammation (reduced IL-1ß, TNF-α, and IL-6 expression) were reduced by miR-485 in epileptic cells. HIF1α and PFKFB3 expression was reduced by HDAC5 knockdown in cells, which was recapitulated in vivo. Thus, miR-485 alleviates neuronal damage and epilepsy by inhibiting HDAC5, HIF1α, and PFKFB3.

Design and biological evaluation of phenyl imidazole analogs as hedgehog signaling pathway inhibitors.

The hedgehog (Hh) signaling pathway is involved in diverse aspects of cellular events. Aberrant activation of Hh signaling pathway drives oncogenic transformation for a wide range of cancers, and it is therefore a promising target in cancer therapy. In the principle of association and ring-opening, we designed and synthesized a series of Hh signaling pathway inhibitors with phenyl imidazole scaffold, which were biologically evaluated in Gli-Luc reporter assay. Compound 25 was identified to possess high potency with nanomolar IC50 , and moreover, it preserved the inhibition against wild-type and drug-resistant Smo-overexpressing cells. A molecular modeling study of compound 25 expounded its binding mode to Smo receptor, providing a basis for the further structural modification of phenyl imidazole analogs.

Oral Mucosa vs. Penile Skin Flap in Substitution Urethroplasty for Anterior Urethral Strictures: A Systematic Review and Meta-Analysis.

Background: The purpose of this study is to compare the effectiveness and safety of oral mucosa and penile skin flaps in the treatment of anterior urethral stricture. Methods: This meta-analysis was carried out according to the principle of preferred reporting items for systematic reviews and meta-analysis (PRISMA) and registered at PROSPERO (CRD42021277688). The Cochrane Library, PubMed, Embase, CKNI databases were searched and reviewed up to Sep 2021. Quality evaluation was performed with Newcastle-Ottawa Scale (NOS) system for non-randomized studies and Cochrane stools for randomized studies. Data synthesis was conducted with RevMan 5.4 software (Cochrane) and a Stata 15.0 environment (Stata Corpor, College Station, TX, USA). Results: After the research screening, eight studies (comprising 445 patients) were finally included in the quantitative analysis. In the success rate comparison, there was no significant difference between oral mucosa and penile skin flaps (oral mucosa vs. penile skin flap, Mantel-Haenszel statistic [M-H] fixed model, OR: 0.80, 95% CI: 0.47-1.34, P = 0.39). There was no significant difference in the post-operative complication comparison (oral mucosa vs. penile skin flap, Mantel-Haenszel statistic [M-H] fixed model, OR: 0.68, 95% CI: 0.40-1.16, P = 0.15). However, considering that the site of oral mucosa is far from the anterior urethra, it may have advantages in operation time through simultaneous operations (oral mucosa vs. penile skin flap, MD: -40.05, 95% CI: -79.42, -0.68, P = 0.046). Conclusion: When the oral mucosal graft was used in the anterior urethra urethroplasty, it had a similar success rate and post-operative complication rate, and oral mucosa substitution had a shorter operation time. This evidence-based medical research further supports the view that oral mucosa is the preferred substitution material for the anterior urethra urethroplasty.

Histone Deacetylase 3 Aggravates Type 1 Diabetes Mellitus by Inhibiting Lymphocyte Apoptosis Through the microRNA-296-5p/Bcl-xl Axis.

Type 1 diabetes mellitus (T1DM) is a chronic autoimmune disease characterized by immune-mediated destruction of pancreatic beta-cells. Multiple microRNAs (miRNAs) have been implicated in T1DM pathogenesis. Although histone deacetylase 3 (HDAC3) has been reported to be involved in T1DM, the underlying mechanisms remain to be further elucidated. This study was designed to investigate the potential regulatory role of Hdac3 on T1DM progression. The expression of miR-296-5p and B-cell leukemia-XL (BCL-XL) was determined using RT-qPCR and Western blot assay in peripheral blood mononuclear cells (PBMCs) of patients with T1DM, tumor necrosis factor-α (TNF-α)- and cycloheximide (CHX)-induced cell model, and streptozotocin (STZ)-induced rat model. The binding affinity between miR-296-5p and Bcl-xl was verified by using dual-luciferase reporter gene assay, and the binding between Hdac3 and the promoter region of miR-296-5p was validated using chromatin immunoprecipitation assay. Western blot analysis and flow cytometry were conducted to assess the apoptotic events of lymphocytes. miR-296-5p expression was downregulated while BCL-XL expression was upregulated in PBMCs of patients with T1DM. An adverse correlation was identified between miR-296-5p and Bcl-xl in mouse TE15 B lymphocytes. Bcl-xl was further validated to be targeted and negatively regulated by miR-296-5p in 293 T cells. Hdac3 inhibited miR-296-5p expression by binding to its promoter region. The effects of overexpressed Hdac3 on lymphocyte apoptosis was counterweighed via downregulation of Bcl-xl or upregulation of miR-296-5p, the mechanism of which was further validated in a rat model of DM. Taken together, the Hdac3-mediated upregulation of Bcl-xl via inhibiting miR-296-5p promoter activity enhanced the anti-apoptotic capacity of lymphocytes to accelerate the occurrence of T1DM.

NF-κB inhibits the occurrence of type 1 diabetes through microRNA-150-dependent PUMA degradation.

AIMS: Type 1 diabetes (T1D) is the most common autoimmune disease that affects a global scale. Accumulating evidence has indicated, nuclear factor kappa B (NF-κB) and some microRNAs (miRNAs) as important biomarkers participating in the development of T1D. Thus, we aimed to determine the role of NF-κB and miR-150 in the development of T1D and to unravel the molecular mechanism. MAIN METHODS: Non-obese diabetic mice were used for the T1D model establishment by injecting with streptozotocin. Besides, pancreatic islet ß cells, separated from T1D mice, were induced by interferon-γ and tumor necrosis factor-α for 3 days to mimic T1D damage. The expression of NF-κB p65, miR-150, and p53 up-regulated modulator of apoptosis (PUMA) was evaluated by RT-qPCR, while the expression of PUMA, p65, and apoptotic proteins in pancreatic islet ß cells were determined by western blot analysis. Besides, inflammatory factors IL-17A, IL-2, IFN-γ, and IL-4 were detected by ELISA. The relationship among NF-κB, miR-150, and PUMA was analyzed by the dual-luciferase reporter gene, chromatin- and RNA-immunoprecipitation assays, respectively. KEY FINDINGS: Restoration of NF-κB reduced the incidence of T1D in mice. Over-expressed NF-κB inhibited the release of inflammatory factors and apoptosis in pancreatic islet ß cells. PUMA was confirmed to be a potential target gene of miR-150. miR-150 suppressed PUMA to inhibit the T1D-induced inflammation and ß cell apoptosis whereas NF-κB activated the miR-150 expression by binding to the miR-150 promoter, thereby preventing the T1D-induced inflammation and ß cell apoptosis. SIGNIFICANCE: NF-κB/miR-150/PUMA may serve as potential therapeutic targets for T1D.

Angiotensin II promotes podocyte injury by activating Arf6-Erk1/2-Nox4 signaling pathway.

Angiotensin II (Ang II) is a key contributor to glomerular disease by predominantly resulting in podocyte injury, whereas the underlying molecular mechanisms has not been fully understood. This study aimed to investigate if and how ADP-ribosylation factor 6 (Arf6), a small GTP-binding protein, involves Ang II-induced cellular injury in cultured human podocytes. Cellular injury was evaluated with caspase 3 activity, reactive oxygen species (ROS) level and TUNEL assay. Arf6 activity was measured using an Arf6-GTP Pull-Down Assay. Ang II significantly enhanced Arf6 expressions accompanied by increase of Arf6-GTP. The TUNEL-positive cells as well as activated caspase 3, NADPH oxidase 4 protein (Nox4) and ROS levels were dramatically increased in Ang II-treated podocytes, which was prevented by secinH3, an Arf6 activity inhibitor. Induction of ROS by Ang II was inhibited in podocytes with Nox4 knockdown. Ang II-induced elevation of Nox4 and ROS was prevented by Arf6 knockdown. Phpspho-Erk1/2Thr202/Tyr204 levels were upregulated remarkably following Ang II treatment, and Erk inhibitor LY3214996 significantly downregulated Nox4 expression. In addition, Ang II decreased CD2AP expression. Overexpression of CD2AP prevented Ang II-induced upregulation of Arf6-GTP. Our data demonstrated that Ang II promotes ROS production and podocytes injury through activation of Arf6-Erk1/2-Nox4 signaling. We also provided evidence that Ang II activates Arf6 by degradation of CD2AP.

Multifunctional conjugated microporous polymers with pyridine unit for efficient iodine sequestration, exceptional tetracycline sensing and removal.

In this work, two multifunctional conjugated microporous polymers (CMP-LS7-8) were obtained via the Pd-catalyzed Suzuki coupling reactions of 2,4,6-tris(4-bromophenyl)pyridine with two aromatic borates. The Brunauer-Emmett-Teller (BET) surface areas of CMP-LS7-8 were calculated to be 507 and 2028 m2 g-1. CMP-LS7-8 exhibit excellent volatile iodine adsorption about 2.77 and 5.29 g g-1, respectively, and outstanding reversible adsorption. High adsorption capacity should be attributed to an integrated effect by excellent porous characteristics, effective sorption sites, and expanded π-conjugated network. In addition, this platform integrated two functions of sensing and adsorption of tetracycline (TC) into one material. The excellent luminescence of CMP-LS7-8 can be effectively quenched by TC, which demonstrates they can be acted as new sensitive and selective fluorescence probes toward TC. Simultaneously, CMP-LS7-8 also display high adsorption ability of TC. The adsorption kinetics of TC suggested that the process of adsorption followed a pseudo-second-order model, and the adsorption behaviour of these polymers fitted with the Langmuir model. These results suggest that CMP-LS7-8 posess high volatile iodine capture and exceptional TC detection and removal performance, which can be promising candidates for environmental remediation.

MicroRNA-483-3p Promotes Proliferation, Migration, and Invasion and Induces Chemoresistance of Wilms' Tumor Cells.

Wilms' tumor is the most common pediatric renal malignancy. MiRNAs are important regulators in multiple cancers including Wilms' tumor. In this study, we examined the role of miR-483-3p on proliferation, chemosensitivity, migration, and invasion of Wilms' tumor cells. The proliferation of Wilms' tumor cells was examined using WST-1 assay. The migration and invasion of Wilms' tumor cells were evaluated by transwell migration assay and matrigel invasion assay. The protein expression levels were detected by Western blot. The effect of miR-483-3p on doxorubicin-induced apoptosis in Wilms' tumor cells was evaluated by caspase-Glo3/7 assay. Forced expression of miR-483-3p promoted the proliferation, migration, and invasion in Wilms' tumor cells. Meanwhile, miR-483-3p decreased the sensitivity of Wilms' tumor cells after doxorubicin treatment. MiR-483-3p inhibited the doxorubicin-induced apoptosis in Wilms' tumor cells by the regulation of BAX and Bcl-2 expression. Furthermore, miR-483-3p regulated epithelial-mesenchymal transition by affecting the expression of E-cadherin, N-cadherin, snail, and vimentin in Wilms' tumor cells. Further studies showed that the expression levels of PTEN and p-AKT in Wilms' tumor cells were changed after aberrant expression of miR-483-3p by binding to 3'-UTR of PTEN. Our study suggests that miR-483-3p played important roles in proliferation and progression in Wilms' tumor cells and might serve as a potential prognostic biomarker and predict chemotherapy response in Wilms' tumor.

TSP2 acts as a suppresser of cell invasion, migration and angiogenesis in medulloblastoma by inhibiting the Notch signaling pathway.

Medulloblastoma (MB) represents a fatal malignancy often occurring in children. Angiogenesis is a hallmark of the progression of MB. Over the past decade, investigators have attempted to develop more effective and less toxic anti-angiogenic strategies to treat MB. Thrombospondin (TSP) family is observed to be a key regulator of angiogenesis. Thus, the current study aimed to elucidate the function of TSP2 in patients with MB and the underlying mechanism. The expression of TSP2, Notch1 and VEGF in MB and adjacent tissues collected from clinical samples as well as a MB cell line (Daoy) was examined. The results demonstrated that in the MB tissues and Daoy cells, TSP2 was downregulated, while Notch1 and VEGF were upregulated. Then, after the Daoy cells were treated with TSP2 silencing, TSP2 overexpression, or Notch signaling pathway inhibition, a series of in vitro cell experiments were performed to verify the interaction between TSP2 and Notch signaling pathway, and to examine the abilities of cell proliferation, migration, invasion, and tube formation. Upregulation of TSP2 was observed to lead to the downregulation of the Notch signaling pathway. Moreover, cells overexpressing TSP2 exhibited diminished proliferation, invasion, migration, and tube formation. In addition, a significant attenuation of tumor growth and angiogenesis was identified in vivo in the Daoy cells overexpressing TSP2 inoculated in nude mice. Taken together, the key findings of this study revealed the inhibitory role of TSP2 in the development of MB via blockade of the Notch signaling pathway, highlighting its potential as a treatment target for MB treatment.

Retracted: Effects of microRNA-494 on proliferation, migration, invasion, and apoptosis of medulloblastoma cells by mediating c-myc through the p38 MAPK signaling pathway.

Medulloblastoma (MB) is the most prevalent brain tumor that occurs during childhood and originates from cerebellar granule cell precursors. Based on recent studies, the differential expression of several microRNAs is involved in MB, while the role of microRNA-494 (miR-494) in MB remains unclear. Therefore, we conducted this study to investigate the regulative role of miR-494 in MB cells via the p38 mitogen-activated protein kinase (MAPK) signaling pathway by mediating c-myc. In the current study, MB cells were collected and transfected with miR-494 mimic, miR-494 inhibitor, siRNA- c-myc, and miR-494 inhibitor + siRNA-c-myc. The expressions of miR-494, c-myc, p38 MAPK, B-cell lymphoma-2 (Bcl-2), Bcl-2-associated X protein (Bax), interleukin-6 (IL-6), metadherin (MTDH), phosphatase and tensin homolog (PTEN) and survivin were determined. Cell proliferation, cell-cycle distribution, apoptosis, migration, and invasion were evaluated. The results revealed that there was a poor expression of miR-494 and high expression of c-myc in MB tissues. C-myc was determined as the target gene of miR-494. In response to miR-494 mimic, MB cells were found to have increased Bax and PTEN expressions, as well as cell number in G1 phase and cell apoptosis and decreased c-myc, p38 MAPK, Bcl-2, MTDH, IL-6, and survivin expression and cell number count in the S phase, cell proliferation, migration, and invasion. In conclusion, the results demonstrated that the upregulation of miR-494 results in the suppression of cell proliferation, migration, and invasion, while it promotes apoptosis of MB cells through the negative mediation of c-myc, which in turn inactivates the p38 MAPK pathway.

IL-17 enhances oxidative stress in hepatocytes through Nrf2/keap1 signal pathway activation.

Hepatic disease is common worldwide. As apoptosis of hepatocytes is a hallmark of hepatic disease, strategies targeting apoptosis are an effective way to prevent and treat the disease. Oxidative stress is a classic pathway of apoptosis. Increased expression of IL-17 has been found in diverse human liver diseases. The aim of this research was to investigate whether the function of IL-17 influenced hepatocyte-induced H2O2. We found that the expression of IL-17 was enhanced in hepatocyte-induced H2O2 and that IL-17 was down-regulated by siRNA. A TUNEL assay showed that apoptosis was decreased in ΔIL-17-mutant hepatocyte-induced H2O2. Additionally, the ratio of Bax/Bcl-2 was decreased in ΔIL-17-mutant hepatocyte-induced H2O2. Finally, Nrf2/keap1 signal pathway was analyzed, the expression of Nrf2 and keap1 was decreased in ΔIL-17-mutant hepatocyte-induced H2O2. These results suggest that oxidative stress-induced apoptosis was induced and that IL-17 could enhance oxidative stress-induced apoptosis by the Nrf2/keap1 signal pathway in hepatocytes.